Toward Rational Pharmacotherapy for Posttraumatic Stress Disorder: Reprise

Twenty-five years ago, I wrote a special article for the Journal with the same title as this one (1). Posttraumatic stress disorder (PTSD) was only 8 years old as a DSM-III diagnosis, and research on PTSD-related psychobiological alterations was in its infancy. As for randomized controlled trials in PTSD patients, none had been published, although a few were in progress at that time. Instead, the sparse literature on pharmacotherapy for PTSD consisted entirely of open trials and case reports on tricyclic antidepressants, monoamine oxidase inhibitors, antiadrenergics (clonidine and propranolol), lithium, and benzodiazepines. I concluded that article optimistically, stating that there was every reason to hope that emerging psychobiological research would lead to rational pharmacotherapy for PTSD.

Since that time, we have learned that individuals with PTSD exhibit dysregulation in a number of key psychobiological systems; most research has focused on the adrenergic and hypothalamic-pituitary-adrenocortical systems, although there have also been studies of serotonergic, dopaminergic, opioid, glutamatergic, GABA-ergic, cannabinoid, and other mechanisms (2). Unfortunately, it is only recently that such discoveries have stimulated a search for novel pharmacological treatments. Instead of a rational approach, focusing on agents designed to address the unique pathophysiology of PTSD, most randomized controlled trials have followed an industry-dominated empirical approach in which medications with proven effectiveness in other disorders have been tested for their efficacy in PTSD. Randomized controlled trials with antidepressants, most notably selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), dominate the list of published trials. Indeed, two SSRIs have been approved by the U.S. Food and Drug Administration as indicated treatments for PTSD (sertraline and paroxetine), although the remission rate after 12 weeks of treatment is only about 30% (3). This compares quite unfavorably with the remission rates achieved with cognitive-behavioral approaches, such as prolonged exposure and cognitive processing therapies (4). There are probably good reasons for the inferior performance of SSRIs and SNRIs. First of all, they are too nonspecific. Given the number and various (sometimes antagonistic) actions of the many different serotonin (5-HT) receptors, it is probably remarkable that any efficacy at all has been demonstrated with these drug classes. Second, these agents appear to have an overall permissive utility that addresses a transdiagnostic irregularity in 5-HT function—hence their efficacy in a variety of mood, anxiety, obsessive-compulsive spectrum, and trauma- and stress-related disorders. Belated recognition of this fact has recently led to clinical trials with much more selective actions at specific 5-HT receptors. Likewise, clinical trials with antiepileptic drugs acting at glutamatergic or GABA-ergic receptors have been even more disappointing, with the possible exception of topiramate (3). To summarize, the hope expressed in my 1988 article has not disappeared but has been laced with a strong dose of disappointment, caution, and a healthy appreciation for the psychobiological complexity of PTSD. One thing seems clear: dusting off medications developed for other disorders (depression, cardiovascular illness, seizure disorders, schizophrenia, and so on) and giving them to PTSD patients is unlikely to lead to a major breakthrough. A rational rather than an empirical approach is much more likely to produce the results we all hope for.

In that regard, the randomized controlled trial of prazosin conducted by Raskind and colleagues and reported in this issue (5) is an important and refreshing exception to the many previous clinical trials in PTSD recounted above. Raskind et al. began from the theoretical perspective that adrenergic dysregulation has been one of the most robust findings in all PTSD research (2). Narrowing their focus to solid evidence regarding adrenergic disruption of rapid eye movement (REM) sleep (6), these investigators predicted that an adrenergic alpha-1 antagonist, prazosin, would reduce traumatic nightmares and possibly ameliorate other PTSD symptoms as well. Starting with small clinical trials and culminating in this successful randomized controlled trial with 67 recently deployed soldiers with war zone-related PTSD, they have shown that prazosin treatment not only reduces traumatic nightmares but also reduces total PTSD symptom severity. Questions remain about these findings, which I will address shortly. For me the biggest question is why adrenergic antagonists have received so little attention over the years. We’ve known about adrenergic dysregulation in PTSD since 1987 (7), and case reports by Kolb et al. (8) regarding successful PTSD treatment with clonidine and propranolol first appeared even earlier, in 1984. Although there have been two negative randomized controlled trials of guanfacine in Vietnam veteran cohorts with chronic PTSD (3), one would have expected a much more aggressive attempt among PTSD investigators to test adrenergic antagonists. Part of the answer, no doubt, relates to a lack of interest on the part of industry to support research on medications whose patents have expired. Indeed, the prazosin trial was supported by federal funding from the Departments of Veterans Affairs and Defense. Had it not been, it is doubtful that this important clinical trial could have taken place.

As for the results themselves, it is exciting that a large and successful theory-driven randomized controlled trial has finally been conducted and published. Given the moderate success achieved with SSRIs and SNRIs, it is important that clinicians have the option of prescribing a medication for PTSD that acts through a different mechanism. There are still too few evidence-based pharmacological alternatives available (9). It is noteworthy that average reductions in symptom severity following prazosin treatment are considerable. A reduction of 10 points on the Clinician-Administered PTSD Scale (CAPS) is considered clinically significant; in this trial the average CAPS improvement was over 25 points in the prazosin group, compared with 13.3 points for the placebo group. On the other hand, only three of 32 prazosin patients (10.7%) achieved full clinical remission, which is poorer than the 30% remission rates achieved among mostly civilian cohorts treated with sertraline and paroxetine (3). Other questions concern the poorer outcomes of prazosin patients who were also taking SSRIs. Does this indicate that these patients had more chronic and severe PTSD, or that there is an interaction between SSRIs and prazosin that produces poorer outcomes? As the authors point out, this result was found with secondary analyses among a handful of patients. But it is a finding that demands further investigation since it suggests that adjunctive use of prazosin in patients receiving SSRIs (or vice versa) may be counterproductive.

To summarize, these results represent an important advance. I hope that other investigators will turn their attention to other theory-driven novel medications for PTSD as well as to replication of the present findings. I am glad to report that federal funding agencies are supporting such research. Indeed, more than 30 randomized controlled trials are currently under way to test novel medications for the prevention and treatment of PTSD as well as to enhance psychotherapy for the disorder (10). In addition to targeting adrenergic, specific serotonergic (e.g., 5-HT₂) and glutamatergic (both NMDA and AMPA) mechanisms, other medications under investigation act on corticotropin-releasing factor, neuropeptide Y, oxytocin, neurokinins, dopamine, dopamine-beta-hydroxylase, allopregnanolone, hydrocortisone, endocannabinoids, and other psychobiological systems.

And so, 25 years later, I end on an optimistic note with the hope that there will be a greater and more aggressive search by investigators for rational approaches to PTSD pharmacotherapy. I also hope that these investigators will receive the federal and industry support that will be needed for them to succeed.